Antitumor Polycyclic Acridines. 8. Synthesis and Telomerase-Inhibitory Activity of Methylated Pentacyclic Acridinium Salts
Two short routes to novel methylated pentacyclic quinoacridinium salts have been devised. New compounds display telomerase-inhibitory potency (
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| Veröffentlicht in: | Journal of medicinal chemistry 2002-01, Vol.45 (3), p.590-597 |
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| container_end_page | 597 |
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| container_issue | 3 |
| container_start_page | 590 |
| container_title | Journal of medicinal chemistry |
| container_volume | 45 |
| creator | Heald, Robert A Modi, Chetna Cookson, Jenny C Hutchinson, Ian Laughton, Charles A Gowan, Sharon M Kelland, Lloyd R Stevens, Malcolm F. G |
| description | Two short routes to novel methylated pentacyclic quinoacridinium salts have been devised. New compounds display telomerase-inhibitory potency ( |
| doi_str_mv | 10.1021/jm011015q |
| format | Article |
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Synthesis and Telomerase-Inhibitory Activity of Methylated Pentacyclic Acridinium Salts</title><source>MEDLINE</source><source>American Chemical Society Journals</source><creator>Heald, Robert A ; Modi, Chetna ; Cookson, Jenny C ; Hutchinson, Ian ; Laughton, Charles A ; Gowan, Sharon M ; Kelland, Lloyd R ; Stevens, Malcolm F. G</creator><creatorcontrib>Heald, Robert A ; Modi, Chetna ; Cookson, Jenny C ; Hutchinson, Ian ; Laughton, Charles A ; Gowan, Sharon M ; Kelland, Lloyd R ; Stevens, Malcolm F. G</creatorcontrib><description>Two short routes to novel methylated pentacyclic quinoacridinium salts have been devised. New compounds display telomerase-inhibitory potency (<1 μM) in the TRAP assay. 3,11-Difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl]acridinium methosulfate (12d, RHPS4, NSC 714187) has a higher selectivity for triplex and quadruplex DNA structures than the 3,6,8,11,13-pentamethyl analogue (12c, RHPS3, NSC 714186) and a low overall growth-inhibitory activity in the NCI 60 cell panel (mean GI50 13.18 μM); in addition, the activity profile of 12d does not COMPARE with agents of the topoisomerase II class. Compound 12d is soluble in water, stable in the pH range of 5−9, efficiently transported into tumor cells, and is currently the lead structure for further elaboration in this new class of telomerase inhibitor.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm011015q</identifier><identifier>PMID: 11806711</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Acridines - chemical synthesis ; Acridines - chemistry ; Acridines - metabolism ; Acridines - pharmacology ; Antineoplastic agents ; Biological and medical sciences ; Cell Nucleus - metabolism ; Crystallography, X-Ray ; DNA - chemistry ; Enzyme Inhibitors - chemical synthesis ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - metabolism ; Enzyme Inhibitors - pharmacology ; Flow Cytometry ; General aspects ; Humans ; Magnetic Resonance Spectroscopy ; Medical sciences ; Microscopy, Confocal ; Models, Molecular ; Pharmacology. Drug treatments ; Solubility ; Structure-Activity Relationship ; Telomerase - antagonists & inhibitors ; Telomerase - chemistry ; Tumor Cells, Cultured</subject><ispartof>Journal of medicinal chemistry, 2002-01, Vol.45 (3), p.590-597</ispartof><rights>Copyright © 2002 American Chemical Society</rights><rights>2002 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a445t-896cac461a45f8119e61c87d5af61c3e59d3d8cdf983868767ff72a29fabb9873</citedby><cites>FETCH-LOGICAL-a445t-896cac461a45f8119e61c87d5af61c3e59d3d8cdf983868767ff72a29fabb9873</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm011015q$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm011015q$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=13452379$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11806711$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Heald, Robert A</creatorcontrib><creatorcontrib>Modi, Chetna</creatorcontrib><creatorcontrib>Cookson, Jenny C</creatorcontrib><creatorcontrib>Hutchinson, Ian</creatorcontrib><creatorcontrib>Laughton, Charles A</creatorcontrib><creatorcontrib>Gowan, Sharon M</creatorcontrib><creatorcontrib>Kelland, Lloyd R</creatorcontrib><creatorcontrib>Stevens, Malcolm F. G</creatorcontrib><title>Antitumor Polycyclic Acridines. 8. Synthesis and Telomerase-Inhibitory Activity of Methylated Pentacyclic Acridinium Salts</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Two short routes to novel methylated pentacyclic quinoacridinium salts have been devised. New compounds display telomerase-inhibitory potency (<1 μM) in the TRAP assay. 3,11-Difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl]acridinium methosulfate (12d, RHPS4, NSC 714187) has a higher selectivity for triplex and quadruplex DNA structures than the 3,6,8,11,13-pentamethyl analogue (12c, RHPS3, NSC 714186) and a low overall growth-inhibitory activity in the NCI 60 cell panel (mean GI50 13.18 μM); in addition, the activity profile of 12d does not COMPARE with agents of the topoisomerase II class. Compound 12d is soluble in water, stable in the pH range of 5−9, efficiently transported into tumor cells, and is currently the lead structure for further elaboration in this new class of telomerase inhibitor.</description><subject>Acridines - chemical synthesis</subject><subject>Acridines - chemistry</subject><subject>Acridines - metabolism</subject><subject>Acridines - pharmacology</subject><subject>Antineoplastic agents</subject><subject>Biological and medical sciences</subject><subject>Cell Nucleus - metabolism</subject><subject>Crystallography, X-Ray</subject><subject>DNA - chemistry</subject><subject>Enzyme Inhibitors - chemical synthesis</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - metabolism</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Flow Cytometry</subject><subject>General aspects</subject><subject>Humans</subject><subject>Magnetic Resonance Spectroscopy</subject><subject>Medical sciences</subject><subject>Microscopy, Confocal</subject><subject>Models, Molecular</subject><subject>Pharmacology. Drug treatments</subject><subject>Solubility</subject><subject>Structure-Activity Relationship</subject><subject>Telomerase - antagonists & inhibitors</subject><subject>Telomerase - chemistry</subject><subject>Tumor Cells, Cultured</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpt0F1r2zAUBmAxNtas28X-wNDNCr1wqg_bki9D2LpCuwaSXYsTWSLKZKuV5FHv19cloWGwqyM4j14OL0KfKZlTwujVviOUElo9vkEzWjFSlJKUb9GMEMYKVjN-hj6ktCeEcMr4e3RGqSS1oHSG_i767PLQhYhXwY961N5pvNDRta43aY7lHK_HPu9McglD3-KN8aEzEZIpbvqd27oc4jj9yO6PyyMOFt-ZvBs9ZNPilekz_Bvqhg6vwef0Eb2z4JP5dJzn6Nf3b5vlj-L2_vpmubgtoCyrXMim1qDLmkJZWUlpY2qqpWgrsNODm6ppeSt1axvJZS1FLawVDFhjYbttpODn6OKQ-xDD42BSVp1L2ngPvQlDUoKWjPD6BV4eoI4hpWiseoiugzgqStRL0eq16Ml-OYYO2860J3lsdgJfjwCSBm8j9Nqlk-NlxbhoJlccnEvZPL3uIf5W00miUpvVWq3FtWh-Lu_U8pQLOql9GGI_dfefA58BfCKiBA</recordid><startdate>20020131</startdate><enddate>20020131</enddate><creator>Heald, Robert A</creator><creator>Modi, Chetna</creator><creator>Cookson, Jenny C</creator><creator>Hutchinson, Ian</creator><creator>Laughton, Charles A</creator><creator>Gowan, Sharon M</creator><creator>Kelland, Lloyd R</creator><creator>Stevens, Malcolm F. G</creator><general>American Chemical Society</general><scope>BSCLL</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20020131</creationdate><title>Antitumor Polycyclic Acridines. 8. Synthesis and Telomerase-Inhibitory Activity of Methylated Pentacyclic Acridinium Salts</title><author>Heald, Robert A ; Modi, Chetna ; Cookson, Jenny C ; Hutchinson, Ian ; Laughton, Charles A ; Gowan, Sharon M ; Kelland, Lloyd R ; Stevens, Malcolm F. 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Drug treatments</topic><topic>Solubility</topic><topic>Structure-Activity Relationship</topic><topic>Telomerase - antagonists & inhibitors</topic><topic>Telomerase - chemistry</topic><topic>Tumor Cells, Cultured</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Heald, Robert A</creatorcontrib><creatorcontrib>Modi, Chetna</creatorcontrib><creatorcontrib>Cookson, Jenny C</creatorcontrib><creatorcontrib>Hutchinson, Ian</creatorcontrib><creatorcontrib>Laughton, Charles A</creatorcontrib><creatorcontrib>Gowan, Sharon M</creatorcontrib><creatorcontrib>Kelland, Lloyd R</creatorcontrib><creatorcontrib>Stevens, Malcolm F. 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Chem</addtitle><date>2002-01-31</date><risdate>2002</risdate><volume>45</volume><issue>3</issue><spage>590</spage><epage>597</epage><pages>590-597</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>Two short routes to novel methylated pentacyclic quinoacridinium salts have been devised. New compounds display telomerase-inhibitory potency (<1 μM) in the TRAP assay. 3,11-Difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl]acridinium methosulfate (12d, RHPS4, NSC 714187) has a higher selectivity for triplex and quadruplex DNA structures than the 3,6,8,11,13-pentamethyl analogue (12c, RHPS3, NSC 714186) and a low overall growth-inhibitory activity in the NCI 60 cell panel (mean GI50 13.18 μM); in addition, the activity profile of 12d does not COMPARE with agents of the topoisomerase II class. Compound 12d is soluble in water, stable in the pH range of 5−9, efficiently transported into tumor cells, and is currently the lead structure for further elaboration in this new class of telomerase inhibitor.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>11806711</pmid><doi>10.1021/jm011015q</doi><tpages>8</tpages></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2002-01, Vol.45 (3), p.590-597 |
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| subjects | Acridines - chemical synthesis Acridines - chemistry Acridines - metabolism Acridines - pharmacology Antineoplastic agents Biological and medical sciences Cell Nucleus - metabolism Crystallography, X-Ray DNA - chemistry Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - metabolism Enzyme Inhibitors - pharmacology Flow Cytometry General aspects Humans Magnetic Resonance Spectroscopy Medical sciences Microscopy, Confocal Models, Molecular Pharmacology. Drug treatments Solubility Structure-Activity Relationship Telomerase - antagonists & inhibitors Telomerase - chemistry Tumor Cells, Cultured |
| title | Antitumor Polycyclic Acridines. 8. Synthesis and Telomerase-Inhibitory Activity of Methylated Pentacyclic Acridinium Salts |
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